Continuous Multi-Parameter Heart Rate Variability Analysis Heralds Onset of Sepsis in Adults

Background

Early diagnosis of sepsis enables timely resuscitation and antibiotics and prevents subsequent morbidity and mortality. Clinical approaches relying on point-in-time analysis of vital signs or lab values are often insensitive, non-specific and late diagnostic markers of sepsis. Exploring otherwise hidden information within intervals-in-time, heart rate variability (HRV) has been documented to be both altered in the presence of sepsis, and correlated with its severity. We hypothesized that by continuously tracking individual patient HRV over time in patients as they develop sepsis, we would demonstrate reduced HRV in association with the onset of sepsis.

Methodology/Principal Findings

We monitored heart rate continuously in adult bone marrow transplant (BMT) patients (n = 21) beginning a day before their BMT and continuing until recovery or withdrawal (12±4 days). We characterized HRV continuously over time with a panel of time, frequency, complexity, and scale-invariant domain techniques. We defined baseline HRV as mean variability for the first 24 h of monitoring and studied individual and population average percentage change (from baseline) over time in diverse HRV metrics, in comparison with the time of clinical diagnosis and treatment of sepsis (defined as systemic inflammatory response syndrome along with clinically suspected infection requiring treatment). Of the 21 patients enrolled, 4 patients withdrew, leaving 17 patients who completed the study. Fourteen patients developed sepsis requiring antibiotic therapy, whereas 3 did not. On average, for 12 out of 14 infected patients, a significant (25%) reduction prior to the clinical diagnosis and treatment of sepsis was observed in standard deviation, root mean square successive difference, sample and multiscale entropy, fast Fourier transform, detrended fluctuation analysis, and wavelet variability metrics. For infected patients (n = 14), wavelet HRV demonstrated a 25% drop from baseline 35 h prior to sepsis on average. For 3 out of 3 non-infected patients, all measures, except root mean square successive difference and entropy, showed no significant reduction. Significant correlation was present amongst these HRV metrics for the entire population.

Conclusions/Significance

Continuous HRV monitoring is feasible in ambulatory patients, demonstrates significant HRV alteration in individual patients in association with, and prior to clinical diagnosis and treatment of sepsis, and merits further investigation as a means of providing early warning of sepsis.     

Diabetic Patients with Severe Sepsis Admitted to Intensive Care Unit Do Not Fare Worse than Non-Diabetic Patients: A Nationwide Population-Based Cohort Study

Background

We sought to examine whether type 2 diabetes increases the risk of acute organ dysfunction and of hospital mortality following severe sepsis that requires admission to an intensive care unit (ICU).

Methods

Nationwide population-based retrospective cohort study of 16,497 subjects with severe sepsis who had been admitted for the first time to an ICU during the period of 1998–2008. A diabetic cohort (n = 4573) and a non-diabetic cohort (n = 11924) were then created. Relative risk (RR) of organ dysfunctions, length of hospital stay (LOS), 90-days hospital mortality, ICU resource utilization and hazard ratio (HR) of mortality adjusted for age, gender, Charlson-Deyo comorbidity index score, surgical condition and number of acute organ dysfunction, were compared across patients with severe sepsis with or without diabetes.

Results

Diabetic patients with sepsis had a higher risk of developing acute kidney injury (RR, 1.54; 95% confidence interval (CI), 1.44–1.63) and were more likely to be undergoing hemodialysis (15.55% vs. 7.24%) in the ICU. However, the diabetic cohort had a lower risk of developing acute respiratory dysfunction (RR = 0.96, 0.94–0.97), hematological dysfunction (RR = 0.70, 0.56–0.89), and hepatic dysfunction (RR = 0.77, 0.63–0.93). In terms of adjusted HR for 90-days hospital mortality, the diabetic patients with severe sepsis did not fare significantly worse when afflicted with cardiovascular, respiratory, hepatic, renal and/or neurologic organ dysfunction and by numbers of organ dysfunction. There was no statistically significant difference in LOS between the two cohorts (median 17 vs. 16 days, interquartile range (IQR) 8–30 days, p = 0.11). Multiple logistic regression analysis to predict the occurrence of mortality shows that being diabetic was not a predictive factor with an odds ratio of 0.972, 95% CI 0.890–1.061, p = 0.5203.

Interpretation

This large nationwide population-based cohort study suggests that diabetic patients do not fare worse than non-diabetic patients when suffering from severe sepsis that requires ICU admission.     

Association between CD14 Promoter -159C/T Polymorphism and the Risk of Sepsis and Mortality: A Systematic Review and Meta-Analysis

Background

Recent studies on the association between CD14-159C/T polymorphism and sepsis showed inconclusive results. Accordingly, we conducted a comprehensive literature search and a meta-analysis to determine whether the CD14-159C/T polymorphism conferred susceptibility to sepsis or was associated with increased risk of death from sepsis.

Methodology

Data were collected from the following electronic databases: PubMed, Embase, Medline, Web of Knowledge, and HuGE Navigator, with the last report up to June 15, 2012. The odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association. We summarized the data on the association between CD14-159C/T polymorphism and sepsis in the overall population and subgroup by ethnicity and sepsis subtype.

Principal Findings

A total of 16 studies on sepsis morbidity (1369 cases and 2382 controls) and 4 studies on sepsis mortality (731 sepsis patients) met the inclusion criteria for meta-analysis. Overall analysis showed no strong evidences of association with sepsis susceptibility under any genetic model. However, slight associations were found in Asian populations (dominant model: OR = 1.38, 95%CI = 0.96–1.98, P = 0.08) and septic shock patients (dominant model: OR = 1.72, 95%CI 1.05–2.83, P = 0.03; allelic model: OR = 1.52, 95%CI 1.09–2.12, P = 0.01) in the stratified analysis. Moreover, there was borderline association between CD14-159C/T and sepsis mortality under the dominant genetic model (OR = 1.44, 95%CI = 0.98–2.11, P = 0.06).

Conclusions/Significance

This meta-analysis suggests that the CD14-159C/T polymorphism may not be a significant susceptibility factor in the risk of sepsis and mortality. Only weak associations were observed in Asian populations and septic shock patients. More studies based on larger sample sizes and homogeneous sepsis patients are needed to confirm these findings.     

Clinical Deterioration during Antitubercular Treatment at a District Hospital in South Africa: The Importance of Drug Resistance and AIDS Defining Illnesses

Background

Clinical deterioration on drug therapy for tuberculosis is a common cause of hospital admission in Africa. Potential causes for clinical deterioration in settings of high HIV-1 prevalence include drug resistant Mycobacterium tuberculosis (M.tb), co-morbid illnesses, poor adherence to therapy, tuberculosis associated-immune reconstitution inflammatory syndrome (TB-IRIS) and subtherapeutic antitubercular drug levels. It is important to derive a rapid diagnostic work-up to determine the cause of clinical deterioration as well as specific management to prevent further clinical deterioration and death. We undertook this study among tuberculosis (TB) patients referred to an adult district level hospital situated in a high HIV-1 prevalence setting to determine the frequency, reasons and outcome for such clinical deterioration.

Method

A prospective observational study conducted during the first quarter of 2007. We defined clinical deterioration as clinical worsening or failure to stabilise after 14 or more days of antitubercular treatment, resulting in hospital referral. We collected data on tuberculosis diagnosis and treatment, HIV-1 status and antiretroviral treatment, and investigated reasons for clinical deterioration as well as outcome.

Results

During this period, 352 TB patients met inclusion criteria; 296 were admitted to hospital accounting for 17% of total medical admissions (n = 1755). Eighty three percent of TB patients (291/352) were known to be HIV-1 co-infected with a median CD4 count of 89cells/mm³ (IQR 38–157). Mortality among TB patients admitted to hospital was 16% (n = 48). The median duration of hospital admission was 9.5 days (IQR 4–18), longer than routine in this setting (4 days). Among patients in whom HIV-1 status was known (n = 324), 72% of TB patients (n = 232) had an additional illness to tuberculosis; new AIDS defining illnesses (n = 80) were the most frequent additional illnesses (n = 208) in HIV-1 co-infected patients (n = 291). Rifampin-resistant M.tb (n = 41), TB-IRIS (n = 51) and drug resistant bacterial infections (n = 12) were found in 12%, 14% and 3.4% of the 352 cases, respectively.

Interpretation

In our setting, new AIDS defining illnesses, drug resistant M.tb and other drug resistant bacteria are important reasons for clinical deterioration in HIV-1 co-infected patients receiving antitubercular treatment. HIV-1 co-infected patients may be at increased risk of acquiring nosocomial drug resistant pathogens because profound immune suppression results in co-morbid illnesses that require prolonged inpatient admissions. Routine infection control is essential and needs to be strengthened in our setting.     

Evaluation of an Online Platform for Multiple Sclerosis Research: Patient Description,Validation of Severity Scale,and Exploration of BMI Effects on Disease Course

Objectives

To assess the potential of an online platform, PatientsLikeMe.com (PLM), for research in multiple sclerosis (MS). An investigation of the role of body mass index (BMI) on MS disease course was conducted to illustrate the utility of the platform.

Methods

First, we compared the demographic characteristics of subjects from PLM and from a regional MS center. Second, we validated PLM’s patient-reported outcome measure (MS Rating Scale, MSRS) against standard physician-rated tools. Finally, we analyzed the relation of BMI to the MSRS measure.

Results

Compared with 4,039 MS Center patients, the 10,255 PLM members were younger, more educated, and less often male and white. Disease course was more often relapsing remitting, with younger symptom onset and shorter disease duration. Differences were significant because of large sample sizes but small in absolute terms. MSRS scores for 121 MS Center patients revealed acceptable agreement between patient-derived and physician-derived composite scores (weighted kappa = 0.46). The Walking domain showed the highest weighted kappa (0.73) and correlation (rs = 0.86) between patient and physician scores. Additionally, there were good correlations between the patient-reported MSRS composite and walking scores and physician-derived measures: Expanded Disability Status Scale (composite rs = 0.61, walking rs = 0.74), Timed 25 Foot Walk (composite rs = 0.70, walking rs = 0.69), and Ambulation Index (composite rs = 0.81, walking rs = 0.84). Finally, using PLM data, we found a modest correlation between BMI and cross-sectional MSRS (rho = 0.17) and no association between BMI and disease course.

Conclusions

The PLM population is comparable to a clinic population, and its patient-reported MSRS is correlated with existing clinical instruments. Thus, this online platform may provide a venue for MS investigations with unique strengths (frequent data collection, large sample sizes). To illustrate its applicability, we assessed the role of BMI in MS disease course but did not find a clinically meaningful role for BMI in this setting.     

The Continuum of Maternal Sepsis Severity: Incidence and Risk Factors in a Population-Based Cohort Study

Objective

To investigate the incidence and risk factors associated with uncomplicated maternal sepsis and progression to severe sepsis in a large population-based birth cohort.

Methods

This retrospective cohort study used linked hospital discharge and vital statistics records data for 1,622,474 live births in California during 2005–2007. Demographic and clinical factors were adjusted using multivariable logistic regression with robust standard errors.

Results

1598 mothers developed sepsis; incidence of all sepsis was 10 per 10,000 live births (95% CI = 9.4–10.3). Women had significantly increased adjusted odds (aOR) of developing sepsis if they were older (25–34 years: aOR = 1.29; ≥35 years: aOR = 1.41), had ≤high-school education (aOR = 1.63), public/no-insurance (aOR = 1.22) or a cesarean section (primary: aOR = 1.99; repeat: aOR = 1.25). 791 women progressed to severe sepsis; incidence of severe sepsis was 4.9 per 10,000 live births (95% CI = 4.5–5.2). Women had significantly increased adjusted odds of progressing to severe sepsis if they were Black (aOR = 2.09), Asian (aOR = 1.59), Hispanic (aOR = 1.42), had public/no-insurance (aOR = 1.52), delivered in hospitals with <1,000 births/year (aOR = 1.93), were primiparous (aOR = 2.03), had a multiple birth (aOR = 3.5), diabetes (aOR = 1.47), or chronic hypertension (aOR = 8.51). Preeclampsia and postpartum hemorrhage were also significantly associated with progression to severe sepsis (aOR = 3.72; aOR = 4.18). For every cumulative factor, risk of uncomplicated sepsis increased by 25% (95% CI = 17.4–32.3) and risk of progression to severe sepsis/septic shock increased by 57% (95% CI = 40.8–74.4).

Conclusions

The rate of severe sepsis was approximately twice the 1991–2003 national estimate. Risk factors identified are relevant to obstetric practice given their cumulative risk effect and the apparent increase in severe sepsis incidence.     

Effect of Statin Therapy in the Outcome of Bloodstream Infections Due to Staphylococcus aureus: A Prospective Cohort Study

Introduction

Statins have pleiotropic effects that could influence the prevention and outcome of some infectious diseases. There is no information about their specific effect on Staphylococcus aureus bacteremia (SAB).

Methods

A prospective cohort study including all SAB diagnosed in patients aged ≥18 years admitted to a 950-bed tertiary hospital from March 2008 to January 2011 was performed. The main outcome variable was 14-day mortality, and the secondary outcome variables were 30-day mortality, persistent bacteremia (PB) and presence of severe sepsis or septic shock at diagnosis of SAB. The effect of statin therapy at the onset of SAB was studied by multivariate logistic regression and Cox regression analysis, including a propensity score for statin therapy.

Results

We included 160 episodes. Thirty-three patients (21.3%) were receiving statins at the onset of SAB. 14-day mortality was 21.3%. After adjustment for age, Charlson index, Pitt score, adequate management, and high risk source, statin therapy had a protective effect on 14-day mortality (adjusted OR = 0.08; 95% CI: 0.01–0.66; p = 0.02), and PB (OR = 0.89; 95% CI: 0.27–1.00; p = 0.05) although the effect was not significant on 30-day mortality (OR = 0.35; 95% CI: 0.10–1.23; p = 0.10) or presentation with severe sepsis or septic shock (adjusted OR = 0.89; CI 95%: 0.27–2.94; p = 0.8). An effect on 30-day mortality could neither be demonstrated on Cox analysis (adjusted HR = 0.5; 95% CI: 0.19–1.29; p = 0.15).

Conclusions

Statin treatment in patients with SAB was associated with lower early mortality and PB. Randomized studies are necessary to identify the role of statins in the treatment of patients with SAB.     

Microbial Translocation Contribute to Febrile Episodes in Adults with Chemotherapy-Induced Neutropenia

In this study we sought to determine the contribution of microbial translocation to febrile episodes with no attributable microbiological cause (Fever of Unknown Origin, FUO) in an adult febrile neutropaenic cohort. Endotoxin concentrations were measured with the chromogenic Limulus Amoebocyte Assay and used as a direct measure of bacterial products whilst soluble CD14 (sCD14), measured with ELISA was selected as an indicator of the early host response to endotoxins. Endotoxin concentrations in this cohort were generally elevated but did not differ with the presentation of fever. Further stratification of the febrile episodes based on the microbiological findings revealed significantly (p = 0.0077) elevated endotoxin concentrations in FUO episodes compared with episodes with documented bacterial and viral findings. sCD14 concentrations were however, elevated in febrile episodes (p = 0.0066) and no association was observed between sCD14 concentration and microbiological findings. However, FUO episodes and episodes with Gram-negative bacteraemia were associated with higher median sCD14 concentrations than episodes with Gram-positive bacteraemia (p = 0.030). In conclusion, our findings suggest that in the absence of microbiological findings, microbial translocation could contribute to febrile episodes in an adult neutropaenic cohort. We further observed an association between prophylactic antibiotic use and increased plasma endotoxin concentrations (p = 0.0212).     

Multiscale Complexity Analysis of the Cardiac Control Identifies Asymptomatic and Symptomatic Patients in Long QT Syndrome Type 1

The study assesses complexity of the cardiac control directed to the sinus node and to ventricles in long QT syndrome type 1 (LQT1) patients with KCNQ1-A341V mutation. Complexity was assessed via refined multiscale entropy (RMSE) computed over the beat-to-beat variability series of heart period (HP) and QT interval. HP and QT interval were approximated respectively as the temporal distance between two consecutive R-wave peaks and between the R-wave apex and T-wave end. Both measures were automatically taken from 24-hour electrocardiographic Holter traces recorded during daily activities in non mutation carriers (NMCs, n = 14) and mutation carriers (MCs, n = 34) belonging to a South African LQT1 founder population. The MC group was divided into asymptomatic (ASYMP, n = 11) and symptomatic (SYMP, n = 23) patients according to the symptom severity. Analyses were carried out during daytime (DAY, from 2PM to 6PM) and nighttime (NIGHT, from 12PM to 4AM) off and on beta-adrenergic blockade (BBoff and BBon). We found that the complexity of the HP variability at short time scale was under vagal control, being significantly increased during NIGHT and BBon both in ASYMP and SYMP groups, while the complexity of both HP and QT variability at long time scales was under sympathetic control, being smaller during NIGHT and BBon in SYMP subjects. Complexity indexes at long time scales in ASYMP individuals were smaller than those in SYMP ones regardless of therapy (i.e. BBoff or BBon), thus suggesting that a reduced complexity of the sympathetic regulation is protective in ASYMP individuals. RMSE analysis of HP and QT interval variability derived from routine 24-hour electrocardiographic Holter recordings might provide additional insights into the physiology of the cardiac control and might be fruitfully exploited to improve risk stratification in LQT1 population.     

Implementing and Measuring the Level of Laboratory Service Integration in a Program Setting in Nigeria

Background

The surge of donor funds to fight HIV&AIDS epidemic inadvertently resulted in the setup of laboratories as parallel structures to rapidly respond to the identified need. However these parallel structures are a threat to the existing fragile laboratory systems. Laboratory service integration is critical to remedy this situation. This paper describes an approach to quantitatively measure and track integration of HIV-related laboratory services into the mainstream laboratory services and highlight some key intervention steps taken, to enhance service integration.

Method

A quantitative before-and-after study conducted in 122 Family Health International (FHI360) supported health facilities across Nigeria. A minimum service package was identified including management structure; trainings; equipment utilization and maintenance; information, commodity and quality management for laboratory integration. A check list was used to assess facilities at baseline and 3 months follow-up. Level of integration was assessed on an ordinal scale (0 = no integration, 1 = partial integration, 2 = full integration) for each service package. A composite score grading expressed as a percentage of total obtainable score of 14 was defined and used to classify facilities (≤80% FULL, 25% to 79% PARTIAL and <25% NO integration). Weaknesses were noted and addressed.

Results

We analyzed 9 (7.4%) primary, 104 (85.2%) secondary and 9 (7.4%) tertiary level facilities. There were statistically significant differences in integration levels between baseline and 3 months follow-up period (p<0.01). Baseline median total integration score was 4 (IQR 3 to 5) compared to 7 (IQR 4 to 9) at 3 months follow-up (p = 0.000). Partial and fully integrated laboratory systems were 64 (52.5%) and 0 (0.0%) at baseline, compared to 100 (82.0%) and 3 (2.4%) respectively at 3 months follow-up (p = 0.000).

Discussion

This project showcases our novel approach to measure the status of each laboratory on the integration continuum.     

Glycemic Variability Is an Independent Predictive Factor for Development of Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease

Patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) often have metabolic disorders including insulin resistance and type 2 diabetes mellitus (T2DM). We clarified the predictive factors in glucose metabolism for progression of hepatic fibrosis in patients with NAFLD by the 75-g oral glucose tolerance test (75gOGTT) and a continuous glucose monitoring system (CGMS). One hundred sixty-nine patients (68 female and 101 male patients) with biopsy-proven NAFLD with performance with 75gOGTT were enrolled and divided into four groups according to the stage of hepatic fibrosis (F0–3). The proportion of patients with T2DM significantly gradually increased, HbA1c and the homeostasis model assessment of insulin resistance were significantly elevated, and 1,5-anhydroglucitol (1,5-AG) was remarkably decreased with the progression of fibrosis. In the 75gOGTT, both plasma glucose and insulin secretion were remarkably increased with the progression of fibrosis. The only factor significantly associated with advanced fibrosis was 1,5-AG (P = 0.008) as determined by multivariate logistic regression analysis. We next evaluated the changes in blood glucose during 24 hours by monitoring with the CGMS to confirm the relationship between glycemic variability and progression of fibrosis. Variability of median glucose, standard deviation of median glucose (P = 0.0022), maximum blood glucose (P = 0.0019), and ΔMin–max blood glucose (P = 0.0029) were remarkably higher in severe fibrosis than in mild fibrosis.

Conclusion

Hyperinsulinemia and hyperglycemia, especially glycemic variability, are important predictive factors in glucose impairment for the progression of hepatic fibrosis in NAFLD.     

Prosthetic Joint Infection in Patients with Rheumatoid Arthritis: An Outcome Analysis Compared with Controls

Background

Patients with rheumatoid arthritis (RA) have been shown to have an increased susceptibility to the development of prosthetic joint infection (PJI) after hip or knee replacement. However, little information is available on the demographic data, outcome of treatment and prognostic factors in RA patients when compared to those in non-RA patients.

Methods/Principal Findings

We performed a retrospective cohort analysis of all cases of PJI that were treated at our institution between 2002 and 2008. Of 346 episodes of PJI during the study period, 46 (13.3%) occurred in patients with RA. Compared to the non-RA cohort, RA patients with PJI were female predominant (74% vs 27%, p<0.001), younger (median age, 51 vs 63 years, p<0.001) and developed infection earlier (median joint age, 72 vs 128 days, p<0.001). The 2-year survival rate free of treatment failure was lower in RA patients with PJI episodes either treated with débridement (22% vs 52%, p = 0.002) or two-stage exchange (78% vs 95%, p = 0.004). A longer duration of symptoms before débridement surgery (median, 11 vs 5 days, p = 0.015), and absence of antibiotics in bone cement for two-stage exchange (relative risk, 8.0; p = 0.02) were associated with treatment failure in patients with RA.

Discussion

The outcome of PJI in RA patients was generally worse than that in non-RA patients. Risk of treatment failure increased in the setting of delayed débridement and two-stage exchange without the use of antibiotic-impregnated bone cement. These findings highlight the importance of vigilant monitoring and aggressive treatment for PJI in RA patients.     

Neuropsychological and Socio-Occupational Functioning in Young Psychiatric Outpatients: A Longitudinal Investigation

Background

Clinical symptoms and neuropsychological deficits are longitudinally associated with functional outcome in chronic psychiatric cohorts. The current study extended these findings to young and early-course psychiatric outpatients, with the aim of identifying cognitive markers that predict later socio-occupational functioning.

Methods

At baseline, 183 young psychiatric outpatients were assessed. Ninety-three returned for follow-up (M = 21.6 years old; SD = 4.5) with an average re-assessment interval of 21.6 months (SD = 7.0), and primary diagnoses of major depressive disorder (n = 34), bipolar disorder (n = 29), or psychosis (n = 30). The primary outcome measure was cross-validated with various other functional measures and structural equation modelling was used to map out the interrelationships between predictors and later functional outcome.

Results

Good socio-occupational functioning at follow-up was associated with better quality of life, less disability, current employment and being in a romantic relationship. The final structural equation model explained 47.5% of the variability in functional outcome at follow-up, with baseline neuropsychological functioning (a composite of memory, working memory and attentional switching) the best independent predictor of later functional outcome. Notably, depressive and negative symptoms were only associated with functioning cross-sectionally. Diagnosis at follow-up was not associated with functional outcome.

Conclusions

Neuropsychological functioning was the single best predictor of later socio-occupational outcome among young psychiatric outpatients. Therefore, framing psychiatric disorders along a neuropsychological continuum is likely to be more useful in predicting functional trajectory than traditional symptom-based classification systems. The current findings also have implications for early intervention utilising cognitive remediation approaches.     

Severe Maternal Sepsis in the UK, 2011–2012: A National Case-Control Study

Background

In light of increasing rates and severity of sepsis worldwide, this study aimed to estimate the incidence of, and describe the causative organisms, sources of infection, and risk factors for, severe maternal sepsis in the UK.

Methods and Findings

A prospective case-control study included 365 confirmed cases of severe maternal sepsis and 757 controls from all UK obstetrician-led maternity units from June 1, 2011, to May 31, 2012. Incidence of severe sepsis was 4.7 (95% CI 4.2–5.2) per 10,000 maternities; 71 (19.5%) women developed septic shock; and five (1.4%) women died. Genital tract infection (31.0%) and the organism Escherichia coli (21.1%) were most common. Women had significantly increased adjusted odds ratios (aORs) of severe sepsis if they were black or other ethnic minority (aOR = 1.82; 95% CI 1.82–2.51), were primiparous (aOR = 1.60; 95% CI 1.17–2.20), had a pre-existing medical problem (aOR = 1.40; 95% CI 1.01–1.94), had febrile illness or were taking antibiotics in the 2 wk prior to presentation (aOR = 12.07; 95% CI 8.11–17.97), or had an operative vaginal delivery (aOR = 2.49; 95% CI 1.32–4.70), pre-labour cesarean (aOR = 3.83; 95% CI 2.24–6.56), or cesarean after labour onset (aOR = 8.06; 95% CI 4.65–13.97). Median time between delivery and sepsis was 3 d (interquartile range = 1–7 d). Multiple pregnancy (aOR = 5.75; 95% CI 1.54–21.45) and infection with group A streptococcus (aOR = 4.84; 2.17–10.78) were associated with progression to septic shock; for 16 (50%) women with a group A streptococcal infection there was <2 h—and for 24 (75%) women, <9 h—between the first sign of systemic inflammatory response syndrome and a diagnosis of severe sepsis. A limitation of this study was the proportion of women with sepsis without an identified organism or infection source (16.4%).

Conclusions

For each maternal sepsis death, approximately 50 women have life-threatening morbidity from sepsis. Follow-up to ensure infection is eradicated is important. The rapid progression to severe sepsis highlights the importance of following the international Surviving Sepsis Campaign guideline of early administration of high-dose intravenous antibiotics within 1 h of admission to hospital for anyone with suspected sepsis. Signs of severe sepsis in peripartum women, particularly with confirmed or suspected group A streptococcal infection, should be regarded as an obstetric emergency. Please see later in the article for the Editors'' Summary     

White Matter Integrity,Creativity, and Psychopathology: Disentangling Constructs with Diffusion Tensor Imaging

That creativity and psychopathology are somehow linked remains a popular but controversial idea in neuroscience research. Brain regions implicated in both psychosis-proneness and creative cognition include frontal projection zones and association fibers. In normal subjects, we have previously demonstrated that a composite measure of divergent thinking (DT) ability exhibited significant inverse relationships in frontal lobe areas with both cortical thickness and metabolite concentration of N-acetyl-aspartate (NAA). These findings support the idea that creativity may reside upon a continuum with psychopathology. Here we examine whether white matter integrity, assessed by Fractional Anisotropy (FA), is related to two measures of creativity (Divergent Thinking and Openness to Experience). Based on previous findings, we hypothesize inverse correlations within fronto-striatal circuits. Seventy-two healthy, young adult (18–29 years) subjects were scanned on a 3 Tesla scanner with Diffusion Tensor Imaging. DT measures were scored by four raters (α = .81) using the Consensual Assessment Technique, from which a composite creativity index (CCI) was derived. We found that the CCI was significantly inversely related to FA within the left inferior frontal white matter (t = 5.36, p = .01), and Openness was inversely related to FA within the right inferior frontal white matter (t = 4.61, p = .04). These findings demonstrate an apparent overlap in specific white matter architecture underlying the normal variance of divergent thinking, openness, and psychotic-spectrum traits, consistent with the idea of a continuum.     

A Five-Year Experience of Carbapenem Resistance in Enterobacteriaceae Causing Neonatal Septicaemia: Predominance of NDM-1

Treatment of neonatal sepsis has become a challenge with the emergence of carbapenemase-producing bacteria. This study documents the trend of carbapenem susceptibility in Enterobacteriaceae that caused septicaemia in neonates over a five year period (2007–2011) and the molecular characterisation of Enterobacteriaceae resistant to carbapenems and cephalosporins. Hundred and five Enterobacteriaceae including Escherichia coli (n = 27), Klebsiella pneumoniae (n = 68) and Enterobacter spp. (n = 10) were isolated from blood of septicaemic neonates followed by antibiotic susceptibility tests, determination of MIC values, phenotypic and genotypic detection of β-lactamases. Carbapenem was the most active antimicrobial tested after tigecycline. CTX-M type was the most prevalent ESBL throughout the period (82%). New Delhi Metallo-β-lactamase-1 (NDM-1), which is a recent addition to the carbapenemase list, was the only carbapenemase identified in our setting. Fourteen percent of the isolates possessed bla_NDM-1. Carbapenem non-susceptibility was first observed in 2007 and it was due to loss of Omp F/Ompk36 in combination with the presence of ESBLs/AmpCs. NDM-1 first emerged in E. coli during 2008; later in 2010, the resistance was detected in K. pneumoniae and E. cloacae isolates. NDM-1-producing isolates were resistant to other broad-spectrum antibiotics and possessed ESBLs, AmpCs, 16S-rRNA methylases, AAC(6′)-Ib-cr, bleomycin resistant gene and class 1 integron. Pulsed field gel electrophoresis of the NDM-1-producing isolates indicated that the isolates were clonally diverse. The study also showed that there was a significantly higher incidence of sepsis caused by NDM-1-harbouring isolates in the male sex, in neonates with low birth weight and neonates born at an extramural centre. However, sepsis with NDM-1-harbouring isolates did not result in a higher mortality rate. The study is the first to review the carbapenem resistance patterns in neonatal sepsis over an extended period of time. The study highlights the persistence of ESBLs (CTX-Ms) and the emergence of NDM-1 in Enterobacteriaceae in the unit.     

Organisational Culture in Residential Aged Care Facilities: A Cross-Sectional Observational Study

Background

Organisational culture is increasingly recognised as important for provision of high-quality long-term care. We undertook this study to measure organisational culture in residential aged care facilities in two Australian states.

Methodology/Principal Findings

Cross-sectional observational study in 21 residential aged care facilities in Western Australia (n = 14) and Queensland (n = 7), Australia. Staff and next-of-kin of residents participated. Measurement comprised surveys of facility staff and residents'' next-of-kin, and structured observation of indicators of care quality. Staff tended to rate organisational culture positively. Some qualitative feedback from staff emphasised negative perceptions of communication, leadership and teamwork. Staffing levels were perceived as a dominant challenge, threatening care quality. Direct observation revealed variability within and between facilities but suggested that most facilities (n = 12) were in the typical range, or were quality facilities (n = 8).

Conclusion

There was scope to strengthen organisational culture in participating aged care facilities.     

Dynamic Eye Tracking Based Metrics for Infant Gaze Patterns in the Face-Distractor Competition Paradigm

Objective

To develop new standardized eye tracking based measures and metrics for infants’ gaze dynamics in the face-distractor competition paradigm.

Method

Eye tracking data were collected from two samples of healthy 7-month-old (total n = 45), as well as one sample of 5-month-old infants (n = 22) in a paradigm with a picture of a face or a non-face pattern as a central stimulus, and a geometric shape as a lateral stimulus. The data were analyzed by using conventional measures of infants’ initial disengagement from the central to the lateral stimulus (i.e., saccadic reaction time and probability) and, additionally, novel measures reflecting infants gaze dynamics after the initial disengagement (i.e., cumulative allocation of attention to the central vs. peripheral stimulus).

Results

The results showed that the initial saccade away from the centrally presented stimulus is followed by a rapid re-engagement of attention with the central stimulus, leading to cumulative preference for the central stimulus over the lateral stimulus over time. This pattern tended to be stronger for salient facial expressions as compared to non-face patterns, was replicable across two independent samples of 7-month-old infants, and differentiated between 7 and 5 month-old infants.

Conclusion

The results suggest that eye tracking based assessments of infants’ cumulative preference for faces over time can be readily parameterized and standardized, and may provide valuable techniques for future studies examining normative developmental changes in preference for social signals.

Significance

Standardized measures of early developing face preferences may have potential to become surrogate biomarkers of neurocognitive and social development.     

Multimodality Multiparametric Imaging of Early Tumor Response to a Novel Antiangiogenic Therapy Based on Anticalins

Anticalins are a novel class of targeted protein therapeutics. The PEGylated Anticalin Angiocal (PRS-050-PEG40) is directed against VEGF-A. The purpose of our study was to compare the performance of diffusion weighted imaging (DWI), dynamic contrast enhanced magnetic resonance imaging (DCE)-MRI and positron emission tomography with the tracer [¹⁸F]fluorodeoxyglucose (FDG-PET) for monitoring early response to antiangiogenic therapy with PRS-050-PEG40. 31 mice were implanted subcutaneously with A673 rhabdomyosarcoma xenografts and underwent DWI, DCE-MRI and FDG-PET before and 2 days after i.p. injection of PRS-050-PEG40 (n = 13), Avastin (n = 6) or PBS (n = 12). Tumor size was measured manually with a caliper. Imaging results were correlated with histopathology. In the results, the tumor size was not significantly different in the treatment groups when compared to the control group on day 2 after therapy onset (P = 0.09). In contrast the imaging modalities DWI, DCE-MRI and FDG-PET showed significant differences between the therapeutic compared to the control group as early as 2 days after therapy onset (P<0.001). There was a strong correlation of the early changes in DWI, DCE-MRI and FDG-PET at day 2 after therapy onset and the change in tumor size at the end of therapy (r = −0.58, 0.71 and 0.67 respectively). The imaging results were confirmed by histopathology, showing early necrosis and necroptosis in the tumors. Thus multimodality multiparametric imaging was able to predict therapeutic success of PRS-050-PEG40 and Avastin as early as 2 days after onset of therapy and thus promising for monitoring early response of antiangiogenic therapy.     

Allergies and Diabetes as Risk Factors for Dengue Hemorrhagic Fever: Results of a Case Control Study

Background

The physiopathology of dengue hemorrhagic fever (DHF), a severe form of Dengue Fever, is poorly understood. We are unable to identify patients likely to progress to DHF for closer monitoring and early intervention during epidemics, so most cases are sent home. This study explored whether patients with selected co-morbidities are at higher risk of developing DHF.

Methods

A matched case-control study was conducted in a dengue sero-positive population in two Brazilian cities. For each case of DHF, 7 sero-positive controls were selected. Cases and controls were interviewed and information collected on demographic and socio-economic status, reported co-morbidities (diabetes, hypertension, allergy) and use of medication. Conditional logistic regression was used to calculate the strength of the association between the co-morbidities and occurrence of DHF.

Results

170 cases of DHF and 1,175 controls were included. Significant associations were found between DHF and white ethnicity (OR = 4.70; 2.17–10.20), high income (OR = 6.84; 4.09–11.43), high education (OR = 4.67; 2.35–9.27), reported diabetes (OR = 2.75; 1.12–6.73) and reported allergy treated with steroids (OR = 2.94; 1.01–8.54). Black individuals who reported being treated for hypertension had 13 times higher risk of DHF then black individuals reporting no hypertension.

Conclusions

This is the first study to find an association between DHF and diabetes, allergy and hypertension. Given the high case fatality rate of DHF (1–5%), we believe that the evidence produced in this study, when confirmed in other studies, suggests that screening criteria might be used to identify adult patients at a greater risk of developing DHF with a recommendation that they remain under observation and monitoring in hospital.